Results and limitations

Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8–5.4) for EV and 4.0 mo (3.2–4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9–52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6–39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15–3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01–14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors.

Conclusions

The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.

Take Home Message

Sequential treatment with everolimus or another receptor tyrosine kinase inhibitor (rTKI) may be equally efficacious in terms of progression-free survival and response rate. Randomised comparative trials are needed to better define the treatment algorithms in rTKI-resistant disease.

1. Introduction

During the last few years, efficacious therapeutic options have been developed for patients with metastatic renal cell carcinoma (mRCC). Most patients are treated with receptor tyrosine kinase inhibitors (rTKIs), particularly sunitinib (Sun), based on the results obtained in two meta-analyses [1] and [2]. Inevitably, most of the patients develop tumour resistance to the first rTKI therapy and therefore require further sequential therapy.

Based on a phase 3 trial, everolimus (EV) is an efficacious treatment option after failure of vascular endothelial growth factor receptor (VEGFr) targeted therapy, particularly rTKI treatment [3]. Current guidelines for the treatment of mRCC have adopted EV as the treatment of choice after VEGF failure [4] and [5]. However, some limited evidence suggests that following failure of one VEGFr targeted agent, patients may still have the potential to respond to another VEGFr inhibitor. Particularly rTKIs such as Sun and sorafenib (Sor) have been applied in sequence, although the data of a phase 2 study suggested limited efficacy of this sequencing regimen [6]. Largely retrospective data form the basis for the sequential use of Sun and Sor or vice versa [7], [8], [9], [10], [11], and [12]. However, studies sufficiently comparing different sequence options are still lacking.

In the context of insufficient comparative data on the best sequence of targeted treatments in mRCC patients, we collected the data of patients treated with two common sequence options: rTKI therapy followed by EV (rTKI-EV) versus rTKI therapy followed by another rTKI (rTKI-rTKI) in two treatment centres. The aim of our retrospective study was to compare these sequence options in terms of efficacy and toxicity.

2. Patients and methods

We retrospectively reviewed patients treated with first rTKI therapy (Sun or Sor) at two large academic centres between 2005 and 2010. Patients receiving the sequence rTKI-EV or rTKI-rTKI were included in this study. Either Sun or Sor was allowed as first rTKI treatments, so the rTKI-rTKI sequence subgroup included patients treated with Sun-Sor or vice versa, and the rTKI-EV subgroup included Sun-EV or Sor-EV. Further therapy lines were individualised and included EV, temsirolimus, dovitinib, interferon α, or bevacizumab plus interferon α. Immunotherapy was the only therapy allowed prior to rTKI treatment and was not considered as a targeted therapy line. Sun was administered daily either as 50mg orally over 4 wk followed by a 2-wk washout period. Stepwise dose reductions by 12.5mg were allowed in case of toxicity. Sor was administered continuously at a full dose of 400mg orally twice a day with allowed dose reduction by 200mg. Dosing for EV was 10mg daily (dose reductions to 5mg daily). All agents were given until progression, death, or intolerable toxicity. Response assessment by computed tomography (CT) or magnetic resonance imaging (MRI) scans was done every 10–12 wk according to the standard Response Evaluation Criteria in Solid Tumours (v.1.0) [13]. Toxicity was graded according to the Common Toxicity Criteria for Adverse Events (CTCAE).

2.1. Statistics

Associations between main characteristics (age, gender, Memorial Sloan-Kettering Cancer Centre [MSKCC] risk [14], and Eastern Cooperative Oncology Group performance group) and response to treatment were explored using the chi-square test and the Mann-Whitney U test as appropriate. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were applied to explore predictors of PFS, sequential treatment duration, and OS in univariate- and multivariable-adjusted analyses. Predictors of OS and PFS were further tested in stratified Kaplan-Meier analyses whenever appropriate. A p value<0.05 was considered statistically significant. All statistical calculations were performed using SPSS v.18 (IBM Corp, Somers, NY, USA).

3. Results

3.1. Patient characteristics

A total of 108 patients with first rTKI treatment were included in the study. Of these 46 received the rTKI-rTKI sequence, and 62 individuals received the rTKI-EV sequence. The rTKI-rTKI group included Sun-Sor (n=35) and Sor-Sun (n=11); the rTKI-EV group consisted of Sun-EV (n=50) and Sor-EV (n=12). All patients underwent nephrectomy before targeted therapy. Table 1 depicts the main patient characteristics of the study population and by sequence group. There were no statistical significant differences between the two treatment groups (rTKI-rTKI vs rTKI-EV) in terms of main characteristics. However, the number of cases with missing MSKCC risk group was higher among the rTKI-rTKI group. Most patients received Sun as the first rTKI therapy (rTKI-rTKI, 76%; rTKI-EV, 80.6%; p=0.638); the remaining patients were treated with Sor.

3.2. Treatment efficacy

Table 2 provides the data on response assessment. For the first-line rTKI treatment, the objective response rate did not differ significantly by sequence group, whereas disease control rate (CR plus PR plus SD) was significantly lower for the rTKI-rTKI group (56%) than for the rTKI-EV (82%; p=0.005). Consequently, a higher proportion of primary rTKI resistance (best response progressive disease) was encountered in the rTKI-rTKI group (26%) than in the rTKI-EV group (13%; p=0.04). PFS on first-line rTKI was 6.6 mo (rTKI-rTKI group) and 10.6 mo (rTKI-EV; p=0.06). Upon exclusion of patients with primary rTKI resistance, PFS differences were no longer evident among the sequence groups (11.2 mo vs 11.5 mo).

Second-line targeted therapy with either another rTKI or EV appeared to be equally efficacious with a median PFS of 4.0 mo for rTKI and 3.6 mo for EV (p=0.455; Fig. 1). Data on treatment duration and OS are displayed in Table 3. Treatment duration for the entire sequence was 11.0 mo (rTKI-rTKI) and 18.5 mo (rTKI-EV; p=0.051). The median time from diagnosis to treatment was 21.0 mo (95% confidence interval [CI], 17.7–24.3) for rTKI-rTKI and 20.0 mo (10.7–29.3) for rTKI-EV (p=0.766). Interestingly, we observed a statistically significant difference in median OS since first rTKI by sequence group (Table 3 and Fig. 2). After exclusion of all patients with intrinsic rTKI resistance, this difference was still obvious but lost statistical significance (32.2 mo [CI, 23.0–41.4] vs 45.4 mo [CI, 36.7–54.1]; p=0.128). Sensitivity analyses excluding all cases with Sor at first line revealed longer sequence therapy duration and longer OS for the Sun-EV sequence than for the Sun-Sor sequence (Table 3).

3.3. Toxicity

For the sequential treatment groups (rTKI vs EV), no statistically significant differences were observed in the rate of grade 3 or 4 toxicities (CTCAE 3.0) or the rate of toxicity-induced treatment termination (Table 4). Most toxicity-related side effects were manageable, and permanent dose reductions were necessary in 12 patients (26%) of the rTKI group and 4 patients (6%) of the EV group (p=0.006). Toxicity data mirror the known toxicity profile of rTKI and EV, respectively.

4. Discussion

Despite significant improvements in the efficacy of systemic treatment of mRCC patients, the best strategy of sequencing targeted therapies remains a matter of debate. Literally all patients with mRCC inevitably experience tumour progression during first-line treatment necessitating sequential therapy.

In this study we compared frequent sequence strategies. Our data support the notion that both efficacy and safety of the most frequently applied sequential targeted therapies (ie, switching rTKI agents or rTKI followed by EV) may be comparable. Interestingly, however, we observed a significant difference in OS favouring the rTKI-EV sequence option. Given the higher proportion of patients with primary (intrinsic) resistance in the rTKI-rTKI group, selection bias cannot be excluded as a reason for this observation. However, a trend towards improved survival for rTKI-EV was still present upon exclusion of cases with intrinsic rTKI resistance, indicating a potential benefit of an early change of mode of action. Results were confirmed in an analysis restricted to cases with Sun as first rTKI (ie, comparing the Sun-EV sequence and the Sun-Sor sequence).

Prospective data on the best sequential therapy among the available sequence options in mRCC are still lacking. In contrast to our observations, Vickers et al. reported that patients receiving another VEGFr-targeted therapy in the sequence setting may experience a longer PFS compared with those treated with mammalian target of rapamycin (mTOR) inhibitors [15]. However, among the 216 patients, only 24 individuals were treated with mTOR inhibitors, and as few as 3 received EV. Apart from our study, no data exist directly comparing the use of EV and rTKI treatment after failure of first-line rTKI therapy in a relevant number of patients. A prospective phase 2 study reported a median PFS of 4.4 mo and an OS of 16 mo for Sor after failure of Sun or bevacizumab [9]. In a recent study on sequential targeted therapy, a median second-line PFS of 4 mo was reported for 25 patients receiving EV after Sun failure [16]. Although the PFS observed in these studies compares well with our data, OS was usually not reported for the entire sequence of treatments. In line with our study, a number of smaller retrospective trials suggested that the sequential use of Sor and Sun or vice versa may show clinical benefit in mRCC patients [8] and [12], although the only prospective single-arm trial on this sequence option indicated a low efficacy of Sor in the second-line setting [6]. Nonetheless, sequencing VEGFr targeted therapy may be a valid treatment option. Porta et al. recently reported on a multicentre series of 189 patients treated with Sun followed by Sor and vice versa [17]. In this study a longer median duration of sequential therapy was observed for the Sor-Sun sequence. However, the imbalance of important characteristics such as the higher proportion of previous systemic therapy (71% vs 38%) and poor risk patients (32% vs 10%) in the Sun-Sor group may account for this observation. Indeed, another study on registry data did not observe differences in PFS or OS by rTKI sequence [18]. Due to their retrospective nature, the validity of these studies and our observations is limited. In our study, an exploratory subgroup analysis, a trend towards longer PFS and OS estimates was observed for the Sor-Sun sequence compared with the Sun-Sor sequence, but the sample size was too small, and no valid conclusions can be made. Results of ongoing prospective randomised trials comparing sequence options, such as Sun followed by EV versus vice versa (NCT00903174) or Sor versus Tem after failure of Sun (NCT 00474786), are eagerly awaited.

Our study has important limitations. The limited numbers of patients in each group underline the uncertainty of our observations. Due to the fact that some patients were treated outside our centres during first-line therapy, data on MSKCC risk group were missing in a significant number of patients. The imbalanced distribution of relevant variables, such as number of metastatic sites or histologic type and missing data on MSKCC prognostic group, may be additional sources of bias. We cannot exclude a selection bias towards good risk patients due to the relatively high proportion of cytokine-pretreated patients. A novel risk prognosis score has been introduced based on patient data from the targeted therapy era [19] but has not yet been validated. This score cannot be calculated in our patient population because neutrophil count is largely missing.

A number of other factors, such as haemoglobin level, age, brain metastasis, or time from diagnosis to treatment, have an impact on PFS and OS in patients undergoing sequential rTKI treatment [7]. In univariate analyses, significant treatment-related toxicity was associated with inferior PFS in our patients, underscoring the importance of stringent management of adverse events [20] and [21].

A better understanding of the mechanism underlying treatment resistance in mRCC patients will help optimise the treatment strategy. Evasive or acquired tumour resistance may develop via mechanisms like alternative proangiogenic signalling pathways within the tumour, recruitment of bone marrow–derived proangiogenic cells, increased protection of tumour vasculature by pericytes, and increased tumour cell invasiveness to escape oxygen and nutrient deprivation [22]. A countermeasure to overcome acquired tumour resistance could be targeting a different signalling pathway [23], blocking the underlying escape signalling pathway [24], or rechallenging the tumour after restoration of a susceptible tumour microenvironment [25]. Intrinsic (primary) resistance may indicate other as yet undefined pathways. The underlying mechanisms of intrinsic and acquired tumour resistance are complex, and further research is needed.

In our exploratory analysis, first-line Sun treatment was an independent predictor of inferior OS. This observation deserves further study. Sun as a potent antiangiogenic agent may indeed induce an aggressive tumour phenotype [26], [27], and [28], although this hypothesis awaits further confirmation in clinical and translational studies. Intrinsic resistance to first rTKI treatment was a strong independent predictor of OS in our study population. As a consequence, patients with intrinsic rTKI resistance had a low chance of clinical benefit from sequential therapy. These facts underscore that overcoming treatment resistance in mRCC patients (eg, by the development of novel targeting strategies) is key for improving survival perspectives. Upon exclusion of patients with intrinsic rTKI resistance, OS still tended to be longer in the rTKI-EV sequence group. This supports the hypothesis that an early change of mode of action may increase the efficacy of mRCC treatment. However, the switch from VEGFr-targeted therapy to mTOR inhibition may not be sufficient, and targeting of pathways not related to angiogenesis may be necessary to significantly increase treatment efficacy.

5. Conclusions

EV remains the preferred option in rTKI-resistant mRCC according to the evidence available to date. Sequential rTKI therapy with Sun or Sor may provide similar efficacy in terms of PFS and response rate. The trend towards superior OS for the rTKI-EV sequence needs further confirmation in prospective randomised trials. Results from such trials comparing different sequence options are urgently needed to better define the treatment algorithms in rTKI-resistant disease.

Author contributions: Steffen Weikert had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Manfred Johannsen has received honoraria from Pfizer Germany, Bayer Ag, Novartis Germany, Sanofi-Aventis, Wyeth Germany, Glaxo Smith Kline, and Roche Germany. He is a consultant for Novartis Germany, Glaxo Smith Kline, and Pfizer Germany. Kurt Miller is an advisor to Pfizer, Roche, and Novartis. Steffen Weikert is an advisor to Pfizer, Bayer, and Novartis. The other authors have nothing to disclose.

[13]
P. Therasse, S.G. Arbuck, E.A. Eisenhauer, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
J Natl Cancer Inst. 2000;92:205-216
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